P1333: PLASMA EXCHANGE, IMMUNOGLOBULIN &amp; PRE-TRANSPLANT IMMUNOSUPPRESSION: AN EFFECTIVE DESENSITISATION STRATEGY FOR DSA ALLOANTIBODIES IN HAPLOIDENTICAL HCT FOR PAEDIATRIC RED CELL DISORDERS
Authors: D. Dexter, S. Bremathas, K. Hennessy, D. Johnson, T. Petterson, K. Lund, A. Gassas, L. Karnik, J. de la Fuente
Journal: HemaSphere (2022)

Background: Near universal availability of HCT is possible due to the feasibility of haploidentical transplantation [haplo HCT] with the use of post-transplantation cyclophosphamide or TCRαβ CD+19 depletion, enabling HCT for haemoglobinopathies and rare inherited anaemias for whom donors are underrepresented in registries. Patients with these disorders are at increased risk of developing anti-HLA antibodies having often received multiple transfusions pre-transplantation. HLA antibodies constituting donor specific antigens [DSA] affect approximately 15% of haplo HCT [Leffel, 2013] representing a significant cause of primary graft failure [Ciurea, 2009]. An effective desensitisation strategy is necessary as alternative donors for haploidentical HCT are often lacking. Several desensitisation approaches have been developed based on strategies used for solid organ transplantation, yet there exists no consensus in their application to haplo HCT for paediatric haemoglobinopathies where there is a particularly high risk of graft failure [de la Fuente, BBMT 2019, de la Fuente, ASH 2020]. Aims: To assess the efficacy of plasma exchange, high dose immunoglobulin and pre-transplant immunosuppression as a desensitisation strategy for DSA alloantibodies in paediatric patients undergoing haploidentical HCT for red cell disorders. Methods: Seven [17.5%] patients were found to have HLA class I DSA in 40 consecutive related reduced-intensity conditioning haplo HCT with post-transplant cyclophosphamide for red cell disorders performed at St Mary’s Hospital from 2013 to December 2021. The MFI cut off used was 2,000U. Transplant indications included homozygous sickle cell disease [n=5], HbSβ0 thalassaemia [n=1] and Diamond-Blackfan anaemia [n=1]. Median age was eight years [range 3-15 years]. Five children were female. Two patients had two different DSA. Each patient received a regimen based on the John Hopkins protocol [Leffel, 2013], comprising a single dose of rituximab 375mg/kg, four alternate day cycles of single volume plasmapheresis [replacing 100% volume with 5% albumin] and anti-CMV hyperimmune immunoglobulin 100mg/kg on days -16, -14, -12 and -10 before the initiation of the conditioning regimen and a further cycle of single volume plasmapheresis on D -1 and anti-CMV hyperimmune immunoglobulin 100mg/kg, and immunosuppression with tacrolimus and MMF to Day 0. HLA antibodies were measured on Day 0 prior to HSC infusion. If the MFI had not decreased <2000U, two further cycles of single volume plasmapheresis and anti-CMV hyperimmune immunoglobulin 100mg/kg were given on D+1 and D+2. Results: The median MFI at baseline was 5,974 U [range 1,544-22806U]. The protocol was well tolerated and completed without serious adverse events in all patients. Four patients required additional cycles on days +1 and +2. Median MFI at protocol completion was 230U [range 0-769U]. No patient suffered primary graft failure. Median time to neutrophil engraftment was 21 days [range 15-24]. All patients achieved full donor whole blood chimerism on D+28 and wheras there was mixed chimerism in the T cell fraction in three of the patients, this improved over time in all patients and no patient suffered secondary graft failure. Summary/Conclusion: The use of a desensitisation protocol comprising the combination of plasma exchange, high dose immunoglobulin and pre transplant immunosuppression constitutes an effective desensitisation strategy for DSA and abrogates the risk of graft failure in multiply transfused paediatric patients undergoing haploidentical HCT for red cell disorders, enabling HCT where no alternative donor exists.